Perioperative Anaphylaxis

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Official reprint from UpToDate®

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Perioperative anaphylaxis: Clinical manifestations,

etiology, and management
Authors: Jerrold H Levy, MD, FAHA, FCCM, Dennis K Ledford, MD
Section Editor: John M Kelso, MD
Deputy Editors: Anna M Feldweg, MD, Nancy A Nussmeier, MD, FAHA
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2023. | This topic last updated: Sep 23, 2022.
INTRODUCTION
Patients undergoing general anesthesia and surgery can experience complex physiologic
changes, which may complicate recognition of an allergic reaction.
The prevalence, etiology, risk factors, clinical manifestations, and acute diagnosis of anaphylaxis
during general anesthesia are reviewed here. The evaluation of a patient who has experienced
perioperative anaphylaxis, skin testing to the drugs that cause immunoglobulin E (IgE)-
mediated reactions, and prevention of recurrent reactions, as well as the treatment of
anaphylaxis from any cause, are discussed separately. (See "Perioperative anaphylaxis:
Evaluation and prevention of recurrent reactions" and "Anaphylaxis: Emergency treatment".)
INCIDENCE
Estimates of the incidence of anaphylaxis during general anesthesia have ranged from 1:350 to
1:20,000, with more recent studies narrowing this range to 1 case for every 1000 to 10,000
episodes of anesthesia [1-8]. The wide variability in estimates of prevalence and incidence
reflects the difficulties in determining the denominator (or the total number of anesthesia
cases), as well as limitations in diagnosing perianesthetic anaphylaxis.
Perioperative anaphylaxis occurs in children less frequently than in adults (ie, approximately 1
in 37,000 cases), but clinical manifestations and culprit drugs are similar [9,10]. The incidence is
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equal in prepubertal girls and boys but greater in adult females than males [1].
MECHANISMS OF ANAPHYLAXIS
Anaphylaxis is an acute, potentially lethal, multisystem syndrome almost always resulting from
the sudden release of mast cell- and basophil-derived mediators into the circulation [11-15].
(See "Pathophysiology of anaphylaxis".)
In this review (and increasingly in the literature), the term "anaphylaxis" applies to all of the
following mechanisms of acute reactions ( table 1) [16]:
● IgE-dependent mechanisms, which account for approximately 60 percent of perioperative

anaphylaxis [17].
● Non-IgE-dependent immunologic mechanisms (formerly called anaphylactoid); included in

this category are reactions mediated by IgG or IgM antibodies or by antigen-antibody
complexes and complement.
● Nonimmunologic mechanisms (formerly called anaphylactoid) involving direct release of

histamine and other mediators from mast cells and basophils [18-22]. The receptor
MRGPRX2 was identified in 2015 and may be responsible for reactions to quinolone
medications (eg, ciprofloxacin), icatibant, general anesthetics (eg, rocuronium,
atracurium), vancomycin, and other drugs with the central tetrahydroisoquinoline (THIQ)
motif [21,23,24].
The various mechanisms leading to activation of mast cells and basophils are increasingly
grouped together under the term "anaphylaxis" because the initial management of these
reactions is the same, regardless of the trigger or mechanism involved, and the clinical severity
of the reactions may be similar [11,12]. In addition, several of the agents that are commonly
implicated in perioperative anaphylaxis, such as neuromuscular-blocking agents, are capable of
causing reactions through more than one mechanism ( table 2).
Despite the similarities, there are important differences in the evaluation, prevention, and
prognosis of the various types of reactions ( table 1):
● Immediate-type skin testing methods (ie, prick-puncture and intradermal techniques) are
only useful in evaluating IgE-mediated reactions.
● The severity of immunologically-mediated reactions may increase with subsequent

administration of the causal agent, while the severity of repeat reactions arising from
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nonimmunologic mechanisms usually remains similar.
● The severity of anaphylaxis associated with specific IgE to the culprit agent is often more
severe than anaphylaxis in which specific IgE cannot be identified [1,25].
● Some IgE-mediated reactions are amenable to desensitization techniques if repeat

anesthesia is required.
● Reactions to radiocontrast media, usually mediated by a nonimmunologic mechanism

related to osmolarity, can be reduced in frequency and intensity with use of iso-osmolar
contrast. Pretreatment with antihistamines and glucocorticoids has not been
demonstrated to provide added preventative benefit when iso-osmolar contrast agents
are used [26]. (See "Patient evaluation prior to oral or iodinated intravenous contrast for
computed tomography", section on 'Prevention'.)
ETIOLOGIES
The more common identifiable causes of perioperative anaphylaxis are antibiotics,

neuromuscular-blocking agents (NMBAs), chlorhexidine, and patent blue and other blue dyes
[8]. However, there is a much longer list of agents that are implicated less commonly and
include blood products, the NMBA reversal agent sugammadex, hypnotic induction agents,
opioids, colloids, and latex. In a significant number of cases, no specific trigger can be
identified.
The best longitudinal data about perioperative anaphylaxis are derived from a series of
multicenter French surveys, which began in the mid-1990s and have continued to the present
[1,27-29]. The causes of perioperative anaphylaxis can be divided into two groups (ie, more
common and less common).
More common — Among cases in which a trigger could be identified, the more common
causes were [1,5,8,29-34]:
● Antibiotics, especially penicillins and cephalosporins (most common cause in several

American and some European studies)
● NMBAs (most common cause in many European studies)
● Chlorhexidine
● Blue dyes (also known as vital dyes, including isosulfan blue, patent blue V, methylene
blue)
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These same medications have been implicated in studies around the world, although the rank
order may differ. Specifically, antibiotics appear to be the most common cause of perioperative
anaphylaxis in the United States and the United Kingdom (UK), while NMBAs are the leading
cause in most European studies [29,35,36].
Antibiotics — Antibiotics, administered before, during, or immediately after anesthesia, are

the leading cause of IgE-mediated perioperative anaphylaxis in the United States, the UK, and
Spain, accounting for approximately 50 percent of reactions [4,8,36-39]. In other European
countries, antibiotics are the second most common cause, and were responsible for 12 to 15
percent of identifiable triggers in the French studies [1,31]. Beta-lactam antibiotics (specifically
penicillins and cephalosporins), which cause IgE-mediated anaphylaxis, and vancomycin, which
usually causes reactions due to direct histamine release from mast cells, are the most common
offenders [30,31,40-43]. Quinolones are infrequently but increasingly incriminated.
Hypersensitivity reactions to these agents are reviewed elsewhere. (See "Penicillin allergy:
Immediate reactions" and "Cephalosporin hypersensitivity: Clinical manifestations and
diagnosis" and "Vancomycin hypersensitivity".)
Neuromuscular-blocking agents — NMBAs (also called muscle relaxants) were the most
common identifiable trigger in the French surveys, accounting for 30 to 70 percent of
anaphylaxis cases [1,29-31,44]. NMBAs can cause anaphylaxis through both IgE-mediated and
nonimmunologic, direct mast cell activation ( table 2) [22,45-47]. Commonly implicated
agents include rocuronium, succinylcholine (also known as suxamethonium), atracurium,
pancuronium, tubocurarine (no longer available in the United States and Canada but used
elsewhere), and vecuronium, although this list may largely reflect the frequency with which
these agents are used [30,31]. In the 2018 United Kingdom prospective registry, succinylcholine
was the most common cause of anaphylaxis among the NMBAs. The reaction rate was equal
among the nondepolarizing agents (ie, rocuronium and cisatracurium), with the occurrence
reflecting the frequency of use [8]. The data also show that for succinylcholine, a depolarizing
NMBA, anaphylaxis more commonly manifests as bronchospasm, whereas atracurium
anaphylaxis presents primarily with hypotension, potentially due to its ability to produce non
immunologic histamine release. Thus, there may be subtle differences in the incidence of
anaphylaxis based on the culprit NMBA.
Allergy to NMBAs is more common in women than men, with three of four reactions occurring
in females [1,44]. IgE sensitization is believed due to cross-reactive tertiary or quaternary
ammonium groups found in both NMBAs and a variety of topical cosmetics and personal
products, as well as certain over-the-counter cough remedies (ie, pholcodine, commonly used in
France, Norway, and other European countries) [48-51]. These ammonium groups are highly
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immunoreactive, multivalent epitopes, which can induce specific IgE antibodies. Sensitization
through exposure to nonmedication agents may explain why allergic reactions to NMBAs
occasionally occur upon initial exposure.
There may be a specific receptor on mast cells activated by NMBAs as well as other drugs, such
as fluoroquinolones and vancomycin [21]. This receptor is designated Mas-related G-protein
coupled receptor X2 (MRGPRX2) and has the capability of binding to a variety of ligands,
resulting in mast cell activation clinically resembling an immune response. In addition to
NMBAs, MRGPRX2 activators include substance P and peptidergic drugs, such as icatibant, used
to treat hereditary angioedema by blocking the bradykinin receptor. A specific inhibitor of
MRGPRX2 in animal models blocks IgE-independent anaphylaxis.
Reactions resulting from IgE-mediated allergy generally are less common, although usually
more severe, than reactions due to other mechanisms such as direct mast cell activation.
Histamine release may be greater with certain NMBAs, such as tubocurarine, mivacurium
(where available), atracurium, and rapacuronium, agents that are seldom used or no longer
available. Rapacuronium was withdrawn from the United States market because it was
implicated in high rates of severe bronchospasm (without other symptoms) [52].
It is possible that the prevalence of sensitization to NMBAs is overestimated. The high rate of
reactions attributed to NMBAs in some studies may be based on positive skin testing results
without confirmatory challenge, and these drugs can cause nonspecific mast cell release,
causing false-positive skin test results. False positive immediate hypersensitivity NMBA skin
tests may also be due to cross-reactivity with other products (cosmetics or the cough medicine
pholcodine) resulting in a positive skin test without clinical allergy [51]. Skin testing to NMBAs
and cross-reactivity among these drugs are discussed separately. (See "Perioperative
anaphylaxis: Evaluation and prevention of recurrent reactions", section on 'Neuromuscular-
blocking agents'.)
Chlorhexidine — Chlorhexidine is a topical antiseptic and surgical scrub that is increasingly

implicated in perioperative anaphylaxis [32,53-61], accounting for 9 percent of the cases
reported in the 2018 UK prospective registry [8]. Reported culprit products include antiseptic
solutions applied to surgical fields (especially mucosal surfaces) and urethral lubricants. Central
venous catheter tips impregnated with chlorhexidine have also been implicated [62]. This
compound is found in nonmedical products such as toothpastes, antiseptic mouthwashes,
bathing solutions, and lozenges. Patients may become sensitized through exposure to such
products.
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Blue dyes — Isosulfan blue dye and the closely-related patent blue V are used in lymph node
mapping, most commonly in patients with breast cancer, genitourinary cancers, and malignant
melanoma. These blue dyes have many other commercial names and are also used as food
dyes [63]. Allergic reactions ranging from mild (blue-colored urticaria or pruritus) to severe
(hypotension) have been reported to both dyes [8,63-72]. In reviewing medical records
regarding exposures relative to perioperative anaphylaxis, it is worth noting that blue dyes are
often not listed on the anesthesia record because they are typically not administered by the
anesthesiologist. Instead, their administration may be described in the operative report,
because they are usually administered by the surgeon [73]. Skin testing is discussed separately.
(See "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions", section on
'Blue dyes'.)
Less common — In the French studies mentioned previously, the following groups of agents
were implicated in less than 10 to 15 percent of reactions [1]:
● Colloids and plasma volume expanders

● Hypnotic induction agents
● Opioids
● Latex
● Other agents
Colloids and plasma expanders — Colloids and plasma expanders, such as dextran or
hetastarch (hydroxyethyl starch [HES]), accounted for approximately 3 percent of identifiable
causes of perioperative anaphylaxis in large series [30,31,74]. These agents are capable of
causing both IgE-mediated and non-IgE-mediated immunologic reactions. Reported rates of
anaphylaxis were <0.1 percent of administrations for each of several preparations [44,75,76].
Hetastarch is used in major surgeries expected to cause significant fluid shifts (eg, trauma).
Dextran is less commonly used as a volume expander, but its antiplatelet effects make it useful
as an adjunct to some vascular procedures.
Human albumin has also been implicated in rare perioperative anaphylaxis, although the
mechanisms have not been explored [77,78]. In addition, gelatin in the plasma expanders
polygeline (eg, Haemaccel) and succinylated gelatins (eg, Gelofusine) has caused IgE-mediated
anaphylaxis [8,79-82]. Gelatin-containing plasma expanders are not in use in the United States,
although they are used in other countries. Some gelatin-induced anaphylaxis may be related to
alpha-gal allergy. (See 'Role of alpha-gal allergy' below.)
Sugammadex — Sugammadex is a highly charged cyclodextrin that rapidly encapsulates and

inactivates steroidal NMBAs (ie, rocuronium or vecuronium) [83-88]. It forms a high affinity
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complex with the NMBA in plasma, thereby reducing the amount of the NMBA available to bind
to nicotinic receptors in the neuromuscular junction, which results in rapid reversal of
neuromuscular blockade. (See "Clinical use of neuromuscular blocking agents in anesthesia",
section on 'Sugammadex'.)
Since its introduction in the European Union in 2008 and subsequently in other countries,
sugammadex has been increasingly implicated as a cause of perioperative anaphylaxis [85]. A
2014 systematic review estimated that anaphylactic reactions occur in 1:3500 to 1:20,000
exposures, while a large 2018 series from the United Kingdom reported a lower rate of 1:64,000
exposures [38,89]. A Japanese study estimated the rate of anaphylaxis to be similar to that
caused by NMBAs, although this may be partly explained by relatively widespread use of
sugammadex in that country [83]. Possible mechanisms for these reactions are discussed
separately. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions",
section on 'Sugammadex'.)
Hypersensitivity reactions to sugammadex typically appear rapidly after intravenous

administration (ie, usually within one minute but sometimes up to several minutes later) and
can occur with first-time administration. Risk factors have not been identified. Reactions can
manifest as clinically significant airway edema and bronchospasm, and if this develops after
extubation, reintubation may be required [90-92]. Repeat administration of sugammadex
following a suspected reaction is contraindicated.
Hypnotic induction agents — Hypnotic induction agents previously accounted for

approximately 2 percent of perioperative anaphylaxis cases, but the prevalence of reactions to
these agents is declining [1]. There are two types of induction agents: barbiturates (eg,
thiopental, methohexital) and nonbarbiturates (eg, propofol, etomidate, ketamine,
benzodiazepines). (See "General anesthesia: Intravenous induction agents".)
● Barbiturates – Allergic reactions to IV barbiturates are becoming an uncommon cause of

perioperative anaphylaxis. Thiopental and thiamylal are no longer available in the United
States but are still used in some other countries. Hypersensitivity reactions to these
agents affect females more often than males [31,45]. Most reactions caused by
barbiturate induction agents are IgE-mediated, although direct mast cell activation has
also been described ( table 2) [19,44,93,94]. There is some immunologic cross-reactivity
among the barbiturates [93].
● Nonbarbiturates – The nonbarbiturate induction agents most commonly used are

propofol and benzodiazepines. Both are rare causes of allergic reactions and there is no
evidence of cross-reactivity between the two.
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Anaphylaxis to propofol can occur but appears to be unrelated to underlying food allergies.
Propofol is a nonbarbiturate induction agent that was initially solubilized in Cremophor
(polyethoxylated castor oil), a vehicle that was implicated in non-IgE-mediated anaphylaxis [95].
Subsequently, the vehicle for propofol was changed to a soybean oil emulsion with egg
phosphatide and glycerol [95-97]. Allergic reactions to these newer preparations are even more
rare. Although allergies to egg or soybean are listed in the product information as
contraindications to use [98], the vast majority of egg-, peanut- and soy-allergic subjects
tolerate propofol [99]. In a study of pediatric patients with egg, peanut, soy, or legume allergy,
children with these allergies tolerated propofol at the same rate as nonallergic children [100].
Benzodiazepines are also nonbarbiturate induction agents. Hypotension following intravenous

administration is a known adverse effect of these agents, although anaphylaxis is very rare
[101]. Benzodiazepines may be capable of activating mast cells in vitro [19]. Skin testing with
benzodiazepines has been reported [102], although the significance of a positive wheal-and-
flare skin reaction is unknown.
Opioids — Opioids used in anesthesia/analgesia are a common cause of flushing and urticaria
following intravenous administration, although opioids rarely cause life-threatening reactions.
Typically, opioids cause limited cutaneous symptoms that are non-IgE-mediated. Morphine or
meperidine can cause degranulation of dermal mast cells and release of histamine and other
mediators, leading to flushing and urticaria, although rarely angioedema, bronchospasm, or
hypotension [22].
Specific IgE to morphine or fentanyl has been implicated in case reports, although skin testing
with opioids requires specific dilutions and cautious interpretation, because direct mast cell
activation, particularly by morphine and codeine, can result in false-positive results [103,104].
Fentanyl and sufentanil are less likely to directly activate mast cells but may cause mast cell
degranulation through specific mu receptors. However, testing with fentanyl and sufentanil
may cause false-positive results due to direct vasodilation [105]. Skin testing to opioids is
reviewed separately. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent
reactions", section on 'Opioids'.)
Latex — Natural rubber latex historically has accounted for approximately 20 percent of
perioperative anaphylaxis cases and is still a common cause in countries in which latex gloves
are used routinely [1,30,31]. However, exposure to latex has been dramatically reduced in most
surgical suites in the United States and other countries. The 2018 United Kingdom national
registry reported no cases of latex allergy among 266 patients with grade 3 or 4 perioperative
anaphylaxis, possibly due to awareness of medical personnel and patients regarding this
possibility, as well as increasing use of latex-free materials in hospital settings [8,106].
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Anaphylaxis to latex is an IgE-mediated process resulting from the formation of specific IgE
against proteins from natural rubber latex. There are a variety of potential sources of latex in
surgical and procedural settings ( table 3). The most common sources of significant latex
exposure in the perioperative setting are flexible items from which latex allergen is easily eluted
and that have prolonged contact with skin or mucosal surfaces, such as:
● Gloves (sterile and exam)

● Drains (Penrose and others)
● Catheters (indwelling, straight, and condom)
Hard rubber items, such as straps, tubing, and blood pressure cuffs, elute little or no latex
protein and do not contact patient tissues to the same extent as surgical gloves, catheters, and
drains. Items that are usually latex-free include bags used in manual ventilation, leg straps for
catheter bags, bandages and adhesive pads, tape, electrode pads, endotracheal tubes, infusion
sets and ports, and suction catheters.
Reactions to latex tend to occur later in surgical procedures (eg, 30 minutes or more after the
start of the intervention). Symptoms may develop after visceral surfaces have been handled or
manipulated by surgeons wearing latex gloves.
Latex allergy is more likely in subjects with repeated exposure to latex gloves or catheters from
prior surgeries or from occupational use, especially children with spina bifida and health care
workers [107]. Sensitization to latex can occur as a result of contact with nonmedical sources of
latex as well (eg, condoms, balloons, household gloves), and reactions are not limited to
patients in high-risk groups. Latex allergy is reviewed in detail separately. (See "Latex allergy:
Epidemiology, clinical manifestations, and diagnosis" and "Latex allergy: Management".)
Other agents — A variety of other medications and agents have been implicated in
anaphylaxis or reactions resembling anaphylaxis [5,18]. Collectively, these other agents account
for less than 5 percent of all episodes of perioperative anaphylaxis [1]. Some of these agents
are not administered by the anesthesiologist, but awareness of their potential to cause
anaphylaxis is necessary for prompt recognition and treatment [106]. Skin testing protocols for
some of these agents are discussed separately (see "Perioperative anaphylaxis: Evaluation and
prevention of recurrent reactions", section on 'Skin testing to specific agents'):
● Radiocontrast agents (see "Diagnosis and treatment of an acute reaction to a radiologic

contrast agent")
● Blood transfusion (see "Immunologic transfusion reactions")
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● Metabisulfites and bisulfites used as preservatives in medications [108-112]
● Nonsteroidal anti-inflammatory drugs (see "NSAIDs (including aspirin): Allergic and

pseudoallergic reactions")
● Povidone in the topical antiseptic povidone-iodine [113,114]
● Bacitracin used in irrigation solutions [115-119]
● The sterilization agents ethylene oxide and ortho-phthalaldehyde (Cidex OPA [brand
name]) [120-125]
● Streptokinase or urokinase [126,127]
● Chymopapain (used in herniated disc surgery) and papain [128-131]
● Insulin [132,133] (see "Hypersensitivity reactions to insulins")
● Local anesthetics [134,135] (see "Allergic reactions to local anesthetics")
● Protamine, used to reverse heparinization [136-138] (see "Hypersensitivity reactions to

insulins", section on 'Protamine')
● Aprotinin, administered either intravenously or as a component of biologic sealants

[1,20,139,140]
● Hyaluronidase, used to enhance the diffusion of other drugs and agents [141-145]
● Heparin and other anticoagulants: These reactions have been attributed to several
mechanisms, including an IgG immune response to platelet factor 4 [146], as well as IgE-
mediated reactions to unidentified antigens [147] (see 'Role of alpha-gal allergy' below
and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section
on 'Anaphylaxis')
● Gelatin-containing surgical sponges and topical bovine thrombin hemostatic agents

[148,149] (see 'Role of alpha-gal allergy' below)
Role of alpha-gal allergy — Some cases of anaphylaxis attributed to animal-derived

products, such as gelatin-based colloids [150], bovine or porcine heart valves [151], heparin,
and hemostatic agents derived from gelatin (eg, gelfoam powders, sponges, etc), may be
caused by allergy to the carbohydrate moiety galactose-alpha-1,3-galactose (also called alpha-
gal) [152], although there are other potential allergens in these products. Alpha-gal allergy has
been reported in the Southeastern United States, as well as areas of Europe, Asia, and Australia.
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Alpha-gal is present in the tissues of all mammalian species except catarrhines (ie, primates
including humans, chimpanzees, baboons, macaques, orangutans, and other old world
monkeys but not new world monkeys). Thus, catarrhines can develop an allergy to tissues and
material derived from other mammals. The risk of alpha-gal allergy may be suspected if
patients report delayed allergic reactions following ingestion of mammalian meats, most
commonly beef, pork, and lamb. Reactions range in severity from transient urticaria to
anaphylaxis and are typically delayed by several hours. Understanding of the role of alpha-gal
versus other allergens in these reactions is evolving and the prevalence of this allergy is
uncertain and varies regionally and seasonally. A positive history would not necessarily
preclude the use of animal-derived products, but the surgical team should have increased
vigilance so that reactions are detected promptly. Case reports have described successful use of
premedications as well [153]. Alpha-gal allergy is discussed in more detail separately. (See
"Allergy to meats", section on 'Alpha-gal'.)
RISK FACTORS
Risk factors for perioperative anaphylaxis include female sex (for certain medications), mast cell
disorders, multiple past surgeries or procedures (especially for latex, neuromuscular-blocking
agents [NMBAs], and ethylene oxide), and history of anaphylaxis, allergic drug reactions, or
other allergic conditions (such as asthma, eczema, or hay fever). In addition, a 2018 registry
identified obesity, a higher level on the American Society of Anesthesiologists Physical Status
Classification system ( table 4), and beta-blocker and/or angiotensin-converting enzyme
inhibitor therapy as risk factors for death or cardiac arrest among 286 cases of more severe
perioperative anaphylaxis [8]. However, even in patients at increased risk, perioperative
anaphylaxis is an uncommon event.
● Patients with asthma or chronic obstructive pulmonary disease are at greater risk for fatal
anaphylaxis from a variety of causes and may be at higher risk for perioperative
anaphylaxis, although data are mixed [1,7,154,155].
● Females are at higher risk than males for reactions to NMBAs and hypnotic induction
agents, although reactions are equal for males and females before adolescence.
● Previous medication reactions nonspecifically increase the possibility of future adverse

medication reactions, and multiple previous drug reactions pose a proportionately greater
risk.
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● Patients with multiple past surgeries or other procedures may be at increased risk for
latex allergy and reactions to NMBAs. (See "Latex allergy: Epidemiology, clinical
manifestations, and diagnosis", section on 'Diagnosis'.)
● Certain types of surgeries, including transplants and hematologic, cardiac, or vascular

procedures, were associated with higher risk in one series [7].
● Patients with mast cell disorders, including hereditary alpha tryptasemia, idiopathic mast
cell activation syndrome, monoclonal mast cell activation disorder, and systemic
mastocytosis, are at increased risk for clinically significant mast cell-mediator release from
a variety of stimuli, including the administration of medications that cause nonspecific
mast cell activation and physiologic events during surgery (eg, handling of the bowel,
extremes of temperature) [156]. Thus, these patients require specific precautionary
management prior to procedures or surgery. (See "Indolent and smoldering systemic
mastocytosis: Management and prognosis", section on 'Preparation for medical, surgical,
and radiologic procedures'.)
CLINICAL MANIFESTATIONS AND DIAGNOSIS
Characteristic signs and symptoms — Anaphylaxis in any setting is diagnosed clinically, based
on the presence of characteristic signs and symptoms that begin suddenly and progress rapidly
in most cases ( table 5). There is no definitive test to prove or disprove anaphylaxis. The
diagnosis of perioperative anaphylaxis is also made clinically.
There are important differences in the presentation of anaphylaxis in an intubated and sedated
patient compared with an ambulatory patient ( table 6) [157,158]:
● Perioperative anaphylaxis is more likely to present as sudden changes in cardiovascular or

respiratory parameters [8,66]. This is because early or mild symptoms, such as itching or
shortness of breath, may go unnoticed if the patient cannot communicate, and skin
symptoms may not be visible if the skin is draped or covered. Cardiovascular collapse,
which can present with signs ranging from hypotension to cardiac arrest, is the first
detected manifestation in up to 50 percent of cases [8,11].
● Hypotension is common during anesthetic induction (especially with propofol).

Recognizing hypotension that is part of anaphylaxis can also be complicated by the effects
of positive pressure ventilation, surgical manipulation, and sympathectomy associated
with spinal/epidural anesthesia. Additional causes of hypotension are discussed below.
(See 'Other causes of hypotension/shock' below.)
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● Bronchospasm may present as a sudden increase in the ventilatory pressure required to

inflate the lungs, an upsloping pattern in the end-tidal carbon dioxide waveform or a
decrease in arterial oxygen saturation.
● Rapidly developing laryngeal edema may present as difficulty with intubation or as

postextubation stridor.
● Tachycardia is a classic cardiovascular sign of anaphylaxis, although bradycardia

occasionally develops later in the reaction if the patient becomes hypoxemic or develops
heart block [159].
As a result of these factors, anaphylaxis may be recognized only when dramatic respiratory and
hemodynamic changes develop.
Timing — Anaphylaxis due to an IgE-mediated reaction usually develops within a few minutes
to approximately 20 minutes following intravenous administration of the causal agent.
Symptoms may manifest later if the trigger was administered orally, intramuscularly, or
through contact with skin or tissues (eg, latex, chlorhexidine). Timing of the reaction with
respect to the onset of anesthesia may provide additional clues to the underlying cause:
● Allergic reactions occurring during the first 30 minutes of anesthesia are more likely due
to antibiotics, neuromuscular-blocking agents, or hypnotic induction agents, because
these agents are given at the start of or prior to the procedure.
● Anaphylaxis presenting after the first 30 minutes of anesthetic induction are more likely
due to agents that are used during or at the conclusion of a surgical procedure, such as
latex, blood products, colloid volume expanders, blue dyes, or protamine.
● Anaphylaxis to sugammadex occurs postoperatively when the agent is administered to

reverse muscle paralysis.
Reactions may also occur after sudden shifts in blood or other fluids, such as removal of a
tourniquet, unclamping of blood vessels, or after uterine manipulation followed by
administration of oxytocin [30,160,161]. If the trigger was administered or applied by the
surgeon (eg, antibiotics in irrigation solutions, topical hemostatic agents, injections of a blue
dye for lymph node identification), the anesthesiologist may not immediately make the
connection between the exposure and the reaction, so a careful review of the events preceding
the reaction with the entire team is critical. (See "Overview of topical hemostatic agents and
tissue adhesives".)
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Severity — Perioperative anaphylaxis tends to be severe and has a higher mortality rate than
anaphylaxis occurring in other settings. In a retrospective review of 266 survivors of
perioperative anaphylaxis, psychological, cognitive, or physical sequelae were reported in one-
third of cases [38]. Estimates of mortality due to perioperative anaphylaxis range from 1.4 to 6
percent, with another 2 percent of patients surviving with anoxic cerebral injury [17,38,155,162].
In contrast, fatal anaphylaxis from all causes is estimated to be 0.7 to 2 percent of cases.
The heightened severity of perioperative anaphylaxis may be attributable to the intravenous

route of drug administration and/or the factors that impair early recognition of reactions.
Another possibility is that individuals receiving anesthesia may be more vulnerable to
physiologic perturbations, especially following spinal/epidural anesthesia, which may cause a
sympathectomy. The concomitant stresses of surgery or illness may also contribute.
IgE-mediated anaphylaxis is generally more severe than non-IgE-mediated anaphylaxis [1],

although both types can be fatal. A review of fatal anaphylaxis from all causes is presented
separately. (See "Fatal anaphylaxis".)
MANAGEMENT
Initial management — The treatment of anaphylaxis during anesthesia is based on prompt

hemodynamic resuscitation that includes epinephrine, fluids, and other strategies ( table 7).
The perioperative/intensive care unit setting is one of the few places that intravenous bolus
epinephrine is used regularly in initial management, outside of advanced cardiac life support
algorithms. For acute shock and cardiopulmonary dysfunction, it is essential to use intravenous
treatment agents, carefully titrated to specific effects. In most other settings, clinicians should
use intramuscular epinephrine for anaphylaxis.
A detailed discussion of anaphylaxis management in other settings is found separately. (See

"Anaphylaxis: Emergency treatment".)
Subsequent allergy evaluation should take place after the patient has recovered fully. This
evaluation is reviewed separately. (See 'Referral for allergy evaluation' below and "Perioperative
anaphylaxis: Evaluation and prevention of recurrent reactions".)
Laboratory tests at the time of the reaction — Blood collected at the time of the reaction (or
shortly after) may reveal elevations in tryptase, a mediator released nearly exclusively by mast
cells and basophils. The release of tryptase can help distinguish anaphylaxis from other
perioperative events, such as cardiogenic shock [163,164]. However, not all episodes of
anaphylaxis result in elevations in tryptase, so a normal tryptase does not exclude anaphylaxis.
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Tryptase was elevated in 68 percent of IgE-mediated reactions and 4 percent of non-IgE-

mediated reactions in the largest French study [1]. Elevations in serum tryptase are most often
detected in cases of anaphylaxis that involve hypotension.
Serum tryptase has a half-life of approximately two hours. Blood for serum tryptase should be
collected as soon as possible after the onset of symptoms [165]. Thirty minutes to three hours
after the onset of symptoms is optimal, although increases may be detectable longer following
massive mast cell activation. Blood for serum tryptase should be collected in a red-top tube,
and a minimum of 1 mL is recommended.
A serum tryptase >11.4 ng/mL is considered elevated. However, an increase in tryptase can
occur with mast cell activation and not exceed the normal range if the baseline level for that
individual is low. An increase in serum total tryptase of 20 percent + 2 ng/mL is accepted as
evidence of mast cell activation. The equation 1.2 x baseline tryptase + 2 ng/mL is used to
calculate the level indicative of mast cell activation [166,167]. For example, if a patient's baseline
tryptase is 2 ng/mL, then a level of 7 ng/mL drawn shortly after a perioperative reaction is
consistent with anaphylaxis. In most cases, the patient's baseline serum tryptase is not known,
but it can be obtained by repeating the serum tryptase several days after the reaction, as
tryptase is rapidly cleared from the circulation. The interpretation of laboratory tests in patients
with anaphylaxis is discussed in more detail elsewhere. (See "Laboratory tests to support the
clinical diagnosis of anaphylaxis".)
Serum that was collected at the time of the reaction for other reasons can sometimes be
retrieved at a later time and assayed. Tryptase is stable in frozen serum for up to one year.
Levels of tryptase can increase dramatically after death due to nonspecific mediator release
during cell death. For postmortem samples, blood should be collected from the femoral artery
or vein and not the heart. (See "Laboratory tests to support the clinical diagnosis of
anaphylaxis", section on 'Fatal anaphylaxis'.)
Assays of other mast cell and basophil products, such as serum and urinary histamine,
histamine metabolites, and prostaglandins, are of limited clinical value. (See "Laboratory tests
to support the clinical diagnosis of anaphylaxis".)
Decisions regarding proceeding with surgery — The decision to proceed with surgery
following anaphylaxis should be individualized depending on the severity of the reaction,
cardiopulmonary stability, and the urgency of the procedural intervention. Ultimately, the
clinicians involved must use clinical judgement to determine the most sensible course of action.
In one retrospective analysis, proceeding with surgery was safe after grade 1 or 2 anaphylactic
reactions (limited to cutaneous signs and/or vital sign changes that are not life-threatening).
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After grade 3 reactions (profound hypotension or severe bronchospasm), the risk of adverse
events attributable to the reaction was higher but did not differ in cases where surgery was
continued or abandoned [168]. Surgical procedures were frequently abandoned after grade 4
reactions (associated with cardiac arrest and/or inability to ventilate) in this study, although
there was no evidence of further harm as a result of proceeding with emergency or partially
completed major surgery. In the 2018 United Kingdom prospective registry, the surgical
procedure was not started or abandoned in more than one-half of the cases with a grade 3 or
higher anaphylactic reaction, including 10 percent where surgery was urgent [38].
REFERRAL FOR ALLERGY EVALUATION
Whom to refer — Patients with suspected perioperative anaphylaxis should prompt

consideration for referral. In contrast, transient, limited flushing or localized erythema (eg,
following vancomycin infusion) is unlikely to represent a significant hypersensitivity reaction
and does not need evaluation [5].
Timing of referral — Patients should be referred to an allergy specialist as soon as possible

after the reaction. It is common practice to defer skin testing for four to six weeks after a
significant reaction, but each case requires data collection and planning before skin testing can
be performed, so prompt referral is helpful. Although an allergy evaluation performed in the
weeks after a reaction is most likely to identify a culprit drug, skin testing performed even years
after a reaction can be informative. Thus, for patients reporting perioperative anaphylaxis years
earlier, an evaluation may still be able to provide some useful information, although the
sensitivity will be lower. The impact of timing on skin testing results is discussed in greater
detail separately. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent
reactions", section on 'Timing of skin testing'.)
Documentation for referral — To maximize the likelihood of identifying the culprit allergen,
the referring anesthesiologist and/or surgeon should provide the following information to the
allergist:
● A detailed description of the event, including all signs and symptoms.
● Copies of anesthesia records and surgical reports.
● The timing of anaphylaxis onset relative to the administration of drugs, blood products,
blue dyes, or other agents or to the performance of procedures (ie, what was happening
during the surgery just before the reaction was detected).
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● The results of serum tryptase levels drawn near the time of the reaction, if available.
● Whether surgical instruments were used in the procedure (because disinfectant chemicals
can be allergens).
● Any type of sterilizing agent (eg, ethylene oxide) used for instruments and disinfectants
(especially chlorhexidine), local anesthetic sprays/gels, dyes, or cements used during the
surgery.
● A description of the composition of any arterial, venous, and urinary catheters and stents
used.
● Whether and when any gelatin-containing volume expanders or hemostatic agents were
used.
● Alternative anesthetic agents available for use in the facility.
Skin testing is the major tool utilized by allergists/immunologists to identify the likely culprit
drug and/or to recommend alternative agents. Although the positive predictive value or
likelihood ratio of positive skin tests for most agents or drugs, other than penicillin, is not well-
defined, this approach has proven successful in a majority of cases. One study of 70 patients
showed that assessment with skin testing in a specialty clinic resulted in 67 patients undergoing
repeat anesthesia without adverse events [169]. The few cases of repeat anaphylaxis were
attributed to either limitations in the historical information provided to the allergy consultant or
to the presence of undetected mast cell disorders. This highlights the importance of providing a
detailed description of the events and timing of drug administration to the consulting allergist.
Ideally, the anesthesiologist should also be prepared to provide small aliquots of anesthetic
drugs to facilitate testing, as these agents are not readily available to other clinicians. However,
the logistics of providing these regulated materials is often a challenge.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of an allergic or anaphylactic reaction during or following general

anesthesia includes a broad list of reactions and physiologic events [5,41,170-172]. Tryptase
levels should be normal in all of these other disorders:
Other causes of respiratory or airway symptoms
● Acute asthmatic reaction in a patient known to have asthma/COPD (see "Anesthesia for
adult patients with asthma", section on 'Intraoperative bronchospasm')
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● Undiagnosed asthma/COPD
● Aspiration
● Inadequate depth of anesthesia
● Endotracheal tube malposition
● Malignant hyperthermia (succinylcholine) (see "Malignant hyperthermia: Diagnosis and
management of acute crisis", section on 'Diagnosis')
● Myotonias and masseter spasm (succinylcholine) (see "Neuromuscular blocking agents
(NMBAs) for rapid sequence intubation in adults for emergency medicine and critical
care", section on 'Trismus')
● Postextubation stridor (see "Respiratory problems in the post-anesthesia care unit
(PACU)", section on 'Upper airway obstruction')
● Pulmonary edema
● Pulmonary embolus (see "Clinical presentation, evaluation, and diagnosis of the
nonpregnant adult with suspected acute pulmonary embolism")
● Tension pneumothorax
● Transfusion-related acute lung injury (TRALI) (see "Transfusion-related acute lung injury
(TRALI)", section on 'Clinical presentation')
(See "Assessment of respiratory distress in the mechanically ventilated patient".)
Other causes of hypotension/shock
● Arrhythmias
● Cardiac tamponade (see "Cardiac tamponade", section on 'Acute cardiac tamponade')
● Cardiogenic shock
● Pulmonary embolus
● Amniotic fluid embolus
● Hemorrhage
● Hyperkalemia
● Overdose of vasoactive drugs
● Partial sympathectomy from spinal/epidural anesthesia
● Sepsis
● Vasovagal reaction
● Venous air embolism (see "Air embolism", section on 'Clinical features')
● Bone cement implantation syndrome (see "Complications of total hip arthroplasty",
section on 'Bone cement implantation syndrome')
Other causes of angioedema
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● Hereditary or acquired C1 esterase inhibitor deficiency (see "Hereditary angioedema:

Acute treatment of angioedema attacks")
● Treatment with angiotensin-converting enzyme inhibitors (see "An overview of
angioedema: Pathogenesis and causes", section on 'Causes')
● Soft tissue swelling due to difficult intubation
Other causes of urticaria — Cold urticaria can occasionally be mistaken for perioperative
anaphylaxis or a drug reaction. Cold urticaria can usually be excluded by the negative results of
an ice cube challenge, except for familial cold urticaria associated with cryopyrin dysfunction
[173]. (See "Cold urticaria".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Drug allergy and
hypersensitivity" and "Society guideline links: Anaphylaxis".)
SUMMARY AND RECOMMENDATIONS
● Anaphylaxis definition and mechanisms – Anaphylaxis is a potentially lethal reaction

usually resulting from the sudden, clinically significant release of mast cell- and/or
basophil-derived mediators into the circulation. Both immunoglobulin E (IgE) and non-IgE-
mediated immune mechanisms have been implicated, and some agents may cause
reactions by more than one mechanism ( table 1 and table 2). (See 'Mechanisms of
anaphylaxis' above.)
● Causes of perioperative anaphylaxis – The more common identifiable causes of

perioperative anaphylaxis are antibiotics, neuromuscular-blocking agents, chlorhexidine,
and blue dyes used in lymph node mapping. However, there is a much longer list of
agents that are implicated less commonly. (See 'Etiologies' above.)
● Risk factors – Risk factors for perioperative anaphylaxis include female sex (for certain
medications), other allergic conditions (eg, asthma, eczema, or hay fever), multiple past
surgeries or procedures (especially for latex), and mast cell disorders. High-risk
procedures include transplants and hematologic, cardiac, or vascular procedures. (See
'Risk factors' above.)
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● Clinical presentation and diagnosis – Perioperative anaphylaxis may exhibit cutaneous,

respiratory, and cardiovascular signs and symptoms, as well as variable involvement of
other organ systems, although these signs may be more difficult to recognize in sedated
or anesthetized patients ( table 6). The diagnosis is clinical. One-half of cases are initially
detected as sudden cardiovascular collapse. Bronchospasm may present as an increase in
the ventilatory pressure required to inflate the lungs or as a decrease in arterial oxygen
saturation. (See 'Clinical manifestations and diagnosis' above.)
● Comparison with anaphylaxis from other causes – Perioperative anaphylaxis tends to

be severe and has a higher mortality rate than anaphylaxis occurring in other settings.
This is at least partly attributable to factors that impair early recognition of anaphylaxis,
such as the inability of the patient to report initial symptoms and coverage of the skin with
surgical drapes. The intravenous administration of triggering drugs and concomitant
stresses of surgery or illness may also contribute. (See 'Severity' above.)
● Epinephrine is critical for treatment – The treatment of anaphylaxis during anesthesia is

based on cardiopulmonary resuscitation that includes prompt administration of
epinephrine and fluid resuscitation ( table 7). Intravenous epinephrine is commonly
used in the operating room while the patient is monitored, and intravenous access is
readily available. (See 'Initial management' above.)
● Obtain a serum tryptase within three hours of the reaction – An increase from
baseline or elevated serum total tryptase, ideally obtained within three hours of a
suspected reaction, is highly suggestive of anaphylaxis, although normal levels do not
exclude the diagnosis. Total tryptase should be compared to a baseline value, collected
prior to surgery or after recovery, to assess the possibility of an increase during the
suspected anaphylaxis episode. An increase of 1.2 x baseline tryptase + 2 ng/mL during
the suspected anaphylaxis is consistent with a mast cell-mediated event. Thus, a normal
acute tryptase value may still suggest mast cell-mediator release if the baseline level is
low. (See 'Laboratory tests at the time of the reaction' above and 'Differential diagnosis'
above.)
● Referral to an allergist – Patients who experience perioperative anaphylaxis should be

referred to an allergy specialist. Clinical history and record review are used to determine
all of the agents to which the patient was exposed leading up to the reaction. The allergist
performs skin testing if feasible and appropriate to identify the likely culprit drug and/or
to recommend alternative agents. This approach allows most patients to undergo future
anesthesia safely. (See 'Referral for allergy evaluation' above.)
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Topic 2077 Version 30.0
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GRAPHICS
Mechanisms of anaphylaxis and pseudoallergic syndromes
Proposed mechanism(s) Characteristics
IgE-mediated activation of mast cells and Can be evaluated with skin tests and/or in
basophils vitro tests for allergen-specific IgE
Examples: Reactions to penicillin and other beta- Requires prior exposure to allergen or cross-
lactams and to neuromuscular-blocking agents reacting allergen
Amenable to desensitization in some
situations
Immunologic mechanisms NOT involving IgE Formerly called anaphylactoid reactions

(mediated by IgG or IgM, antigen:antibody Skin testing and in vitro IgE testing are NOT
complexes, and/or complement) useful
Examples: Reactions to dextran, protamine Pretreatment with glucocorticoids and/or
antihistamines may be helpful
Direct (nonimmunologic) activation of mast Formerly called anaphylactoid reactions

cells and basophils Skin testing and in vitro IgE testing are NOT
Examples: Reactions to radiocontrast agents, useful
opioids, and to neuromuscular-blocking agents Pretreatment with glucocorticoids and/or
antihistamines may be helpful
Slow administration of responsible agent
generally minimizes reactions
IgE: immunoglobulin E; IgG: immunoglobulin G; IgM: immunoglobulin M.
Graphic 57346 Version 11.0
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Some agents capable of causing perioperative anaphylaxis and proposed

mechanisms
Immunologic reactions
Agents Nonimmunologic
IgE-mediated Non-IgE-mediated
Neuromuscular-blocking + – +
agents
Antibiotics + +/– +
(eg, beta-lactams) (eg, vancomycin)
Chlorhexidine + +/– –
Blue dyes (aka vital dyes) + – +/–
Hypnotic induction agents:
Barbiturates + + +
Nonbarbiturates +/– + +
Opioids +/– – +
Colloids and plasma + + +

expanders
Sugammadex + – +/–
Latex + – –
+/–: agent may cause anaphylaxis by this mechanism.
IgE: immunoglobulin E.
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Articles used during surgery or procedures and likelihood of clinically

significant latex content
Items which may contain natural rubber latex:
Gloves (sterile and exam)
Drains (Penrose and others)
Catheters (indwelling, straight, and condom)
Items which are now usually latex-free:
Ambu-bag, airway masks
Catheter leg bag straps
Elastic bandages
Electrode pads
Endotracheal tubes
Intravenous bags, ports, infusion sets
Self-adhesive bandages and adhesive tape
Suction catheters
Adapted with permission from: Chacko T, Ledford D. Peri-anesthetic anaphylaxis. Immunol Allergy Clin N Am 2007; 27:213.
Copyright © 2007 Elsevier.
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American Society of Anesthesiologists Physical Status (ASA PS) Classification

System
ASA PS Examples, including, but not

Definition
classification limited to:
ASA I A normal healthy patient Healthy, nonsmoking, no or minimal

alcohol use.
ASA II A patient with mild systemic disease Mild diseases only without substantive
functional limitations. Current smoker,
social alcohol drinker, pregnancy,
obesity (30<BMI<40), well-controlled
DM/HTN, mild lung disease.
ASA III A patient with severe systemic disease Substantive functional limitations; one
or more moderate to severe diseases.
Poorly controlled DM or HTN, COPD,
morbid obesity (BMI ≥40), active
hepatitis, alcohol dependence or
abuse, implanted pacemaker,
moderate reduction of ejection
fraction, ESKD undergoing regularly
scheduled dialysis, premature infant
PCA <60 weeks, history (>3 months) of
MI, CVA, TIA, or CAD/stents.
ASA IV A patient with severe systemic disease Recent (<3 months) MI, CVA, TIA, or
that is a constant threat to life CAD/stents, ongoing cardiac ischemia
or severe valve dysfunction, severe
reduction of ejection fraction, sepsis,
DIC, ARDS, or ESKD not undergoing
regularly scheduled dialysis.
ASA V A moribund patient who is not Ruptured abdominal/thoracic

expected to survive without the aneurysm, massive trauma,
operation intracranial bleed with mass effect,
ischemic bowel in the face of
significant cardiac pathology or
multiple organ/system dysfunction.
ASA VI A declared brain-dead patient whose

organs are being removed for donor
purposes
The addition of "E" to the numerical status (eg, IE, IIE, etc) denotes Emergency surgery (an
emergency is defined as existing when delay in treatment of the patient would lead to a significant
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increase in the threat to life or body part).
BMI: body mass index; DM: diabetes mellitus; HTN: hypertension; COPD: chronic obstructive
pulmonary disease; ESKD: end-stage kidney disease; PCA: post conceptual age; MI: myocardial
infarction; CVA: cerebrovascular accident; TIA: transient ischemic attack; CAD: coronary artery
disease; DIC: disseminated intravascular coagulation; ARDS: acute respiratory distress syndrome.
ASA Physical Status Classification System (Copyright © 2014) is reprinted with permission of the American Society of
Anesthesiologists, 1061 American Lane, Schaumburg, Illinois 60173-4973.
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Diagnostic criteria for anaphylaxis
Anaphylaxis is highly likely when any ONE of the following three criteria is fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin,
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING:
A. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, hypoxemia)
B. Reduced BP* or associated symptoms of end-organ dysfunction (eg, hypotonia, collapse,

syncope, incontinence)
2. TWO OR MORE OF THE FOLLOWING that occur rapidly after exposure to a LIKELY
allergen for that patient (minutes to several hours):
A. Involvement of the skin mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-
uvula)
B. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, hypoxemia)
C. Reduced BP* or associated symptoms (eg, hypotonia, collapse, syncope, incontinence)
D. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP* after exposure to a KNOWN allergen for that patient (minutes to several
hours):
A. Infants and children - Low systolic BP (age-specific)* or greater than 30% decrease in systolic
BP
B. Adults - Systolic BP of less than 90 mmHg or greater than 30% decrease from that person's
baseline
BP: blood pressure.
* Low systolic blood pressure for children is defined as:

Less than 70 mmHg from 1 month to 1 year
Less than (70 mmHg + [2 x age]) from 1 to 10 years
Less than 90 mmHg from 11 to 17 years
Adapted with permission from: Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and
management of anaphylaxis: summary report-Second National Institute of Allergy and Infectious Disease/Food Allergy and
Anaphylaxis Network symposium. J Allergy Clin Immunol 2006; 117:391. Copyright © 2006 The American Academy of
Allergy, Asthma, and Immunology.
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Differences between perioperative/perianesthesia anaphylaxis and

anaphylaxis in other settings
Manifestations of
In other settings In perioperative settings
anaphylaxis
Upper respiratory Throat tightness, change in Difficulty with intubation

tract/laryngeal edema voice quality
Lower respiratory Shortness of breath, wheezing, Increase in ventilatory pressure

tract/bronchospasm repetitive cough needed to inflate lungs
Increase in end-tidal CO2
Decrease in arterial oxygen

saturation
Cardiovascular Dizziness, tunnel vision Cardiovascular collapse

system/hypotension common (first detected
Collapse without warning signs
manifestation in one-half of
uncommon
cases)
Arrhythmias and cardiac arrest

are more common
Skin Flushing, itching, or urticaria Cutaneous signs and symptoms

(present in >90% of cases) may be absent or present but
hidden by surgical drapes
Patient cannot report itching
In the perioperative setting, patients are usually sedated or anesthetized and unable to report some
of the milder and earlier signs of an allergic reaction. In addition, many exposures are intravenous.
For these reasons, patients are more likely to present with cardiopulmonary symptoms, rather than
cutaneous symptoms.
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Anaphylaxis: Perioperative setting (adult)
Signs (and symptoms, if patient can communicate)
Hypotension/shock.
Tachycardia/arrhythmias.
Dyspnea/wheezing/high peak inspiratory pressure/bronchospasm.
Hypoxemia or decreased O2 saturation noted on pulse oximetry.
Decreased breath sounds.
Angioedema (face, lips, laryngeal stridor).
Hives/itching.
Flushing.
Immediate actions
Call for help. Inform team and surgeon. Get code cart.
Check for possible causes: Stop antibiotics, muscle relaxants, IV contrast, blood products, and
latex exposure.
Administer 100% FiO2.
Secure or establish airway.
For hypotension/shock, give epinephrine bolus (may repeat or escalate dose in one to two
minutes and titrate to effect).
Dosing 10 to 100 mcg per IV bolus.
If no detectable blood pressure, then initiate ACLS protocol and administer fluid bolus
(approximately 25 to 50 mL/kg).
For ongoing hypotension, start IV infusion of epinephrine.
Dosing 2 to 10 mcg/minute, titrated to effect.
Other therapies for anaphylaxis (if signs/symptoms persist)
Albuterol: Four to eight puffs initially for bronchospasm; alternatively, 2.5 mg albuterol in 2.5
mL of saline nebulized for administration via the endotracheal tube.
Methylprednisolone: 125 mg IV or hydrocortisone: 100 mg IV.
H1 antihistamines: Diphenhydramine: 50 mg IV.
H2 antihistamines: Famotidine: 20 mg IV (or cimetidine).
Vasopressin for refractory hypotension (1 to 2 units bolus or infusion).
Norepinephrine infusion for refractory hypotension as an alternative (2 to 10 mcg/minute
titrated to effect).
Continue fluid administrations for refractory hypotension up to 50 mL/kg; after the first two
liters or fluid resuscitation for refractory shock, further hemodynamic monitoring should be
considered.
Consider vasopressin or glucagon (1 to 5 mg slow IV bolus over five minutes) for refractory
shock if patient has received high-dose beta-blockers.
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Echocardiography (transthoracic or transesophageal) to diagnose cause of refractory

hypotension.
Consider and exclude other causes of signs/symptoms
Pneumothorax/tension pneumothorax.
Pericardial tamponade.
Myocardial infarction.
Aspiration.
Pulmonary edema.
Air or pulmonary embolus.
If patient develops cardiovascular collapse
Go to ACLS protocols for:

Asystole/PEA.
VF/VT.
No detectable blood pressure.
Send serum tryptase
Obtain at least 1 mL of blood in a red top tube for serum tryptase assay, ideally within 1 hour,
but may remain elevated up to 3 hours from onset of event. Repeat serum tryptase after 24
hours to establish baseline concentration.
After resuscitation
Observe patient in the intensive care unit recovery room for 12 to 24 hours.
Continue glucocorticoids for 24 hours.
Refer to allergist.
IV: intravenous; FiO2: fraction of inspired oxygen; ACLS: advanced cardiac life support; PEA: pulseless
electrical activity; VF: ventricular fibrillation; VT: ventricular tachycardia.
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Contributor Disclosures
Jerrold H Levy, MD, FAHA, FCCM Consultant/Advisory Boards: Merck [Neuromuscular blockade reversal];
Octapharma [Bleeding]; Werfen [Coagulopathy, bleeding]. All of the relevant financial relationships listed
have been mitigated. Dennis K Ledford, MD Grant/Research/Clinical Trial Support: AstraZeneca
[COPD/Asthma]; Novartis [Urticaria]. Consultant/Advisory Boards: AstraZeneca [Asthma]; BioCryst
[Hereditary angioedema]. Speaker's Bureau: ALK [Allergen immunotherapy]; AstraZeneca [Asthma];
Boehringer-Ingelheim [Asthma]; Genentech [Asthma/urticaria]; Novartis [Asthma/urticaria];
Sanofi/Genzyme [Asthma]. Other Financial Interest: Contributing Editor to 'Ask the Expert' of American
Academy of Allergy Asthma and Immunology [Allergy]; CRC Press for Allergens and Allergen
Immunotherapy, 6th edition [Allergy]; Expert legal review [Latex allergy, metal allergy, asthma, indoor
environment, drug allergy]. All of the relevant financial relationships listed have been mitigated. John M
Kelso, MD No relevant financial relationship(s) with ineligible companies to disclose. Anna M Feldweg,
MD No relevant financial relationship(s) with ineligible companies to disclose. Nancy A Nussmeier, MD,
FAHA No relevant financial relationship(s) with ineligible companies to disclose.
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Perioperative Anaphylaxis

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Perioperative Anaphylaxis

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3/29/23, 3:01 PM 2077

Official reprint from UpToDate®

Perioperative anaphylaxis: Clinical manifestations,

● IgE-dependent mechanisms, which account for approximately 60 percent of perioperative

● Non-IgE-dependent immunologic mechanisms (formerly called anaphylactoid); included in

● Nonimmunologic mechanisms (formerly called anaphylactoid) involving direct release of

● The severity of immunologically-mediated reactions may increase with subsequent

nonimmunologic mechanisms usually remains similar.

● Some IgE-mediated reactions are amenable to desensitization techniques if repeat

● Reactions to radiocontrast media, usually mediated by a nonimmunologic mechanism

The more common identifiable causes of perioperative anaphylaxis are antibiotics,

● Antibiotics, especially penicillins and cephalosporins (most common cause in several

Antibiotics — Antibiotics, administered before, during, or immediately after anesthesia, are

Chlorhexidine — Chlorhexidine is a topical antiseptic and surgical scrub that is increasingly

● Colloids and plasma volume expanders

Sugammadex — Sugammadex is a highly charged cyclodextrin that rapidly encapsulates and

Hypersensitivity reactions to sugammadex typically appear rapidly after intravenous

Hypnotic induction agents — Hypnotic induction agents previously accounted for

● Barbiturates – Allergic reactions to IV barbiturates are becoming an uncommon cause of

● Nonbarbiturates – The nonbarbiturate induction agents most commonly used are

Benzodiazepines are also nonbarbiturate induction agents. Hypotension following intravenous

● Gloves (sterile and exam)

● Radiocontrast agents (see "Diagnosis and treatment of an acute reaction to a radiologic

● Blood transfusion (see "Immunologic transfusion reactions")

● Metabisulfites and bisulfites used as preservatives in medications [108-112]

● Nonsteroidal anti-inflammatory drugs (see "NSAIDs (including aspirin): Allergic and

● Povidone in the topical antiseptic povidone-iodine [113,114]

● Bacitracin used in irrigation solutions [115-119]

● Streptokinase or urokinase [126,127]

● Chymopapain (used in herniated disc surgery) and papain [128-131]

● Insulin [132,133] (see "Hypersensitivity reactions to insulins")

● Local anesthetics [134,135] (see "Allergic reactions to local anesthetics")

● Protamine, used to reverse heparinization [136-138] (see "Hypersensitivity reactions to

● Aprotinin, administered either intravenously or as a component of biologic sealants

● Gelatin-containing surgical sponges and topical bovine thrombin hemostatic agents

Role of alpha-gal allergy — Some cases of anaphylaxis attributed to animal-derived

● Previous medication reactions nonspecifically increase the possibility of future adverse

● Certain types of surgeries, including transplants and hematologic, cardiac, or vascular

CLINICAL MANIFESTATIONS AND DIAGNOSIS

● Perioperative anaphylaxis is more likely to present as sudden changes in cardiovascular or

● Hypotension is common during anesthetic induction (especially with propofol).

● Bronchospasm may present as a sudden increase in the ventilatory pressure required to

● Rapidly developing laryngeal edema may present as difficulty with intubation or as

● Tachycardia is a classic cardiovascular sign of anaphylaxis, although bradycardia

● Anaphylaxis to sugammadex occurs postoperatively when the agent is administered to

The heightened severity of perioperative anaphylaxis may be attributable to the intravenous

IgE-mediated anaphylaxis is generally more severe than non-IgE-mediated anaphylaxis [1],

Initial management — The treatment of anaphylaxis during anesthesia is based on prompt

A detailed discussion of anaphylaxis management in other settings is found separately. (See

Tryptase was elevated in 68 percent of IgE-mediated reactions and 4 percent of non-IgE-

REFERRAL FOR ALLERGY EVALUATION

Whom to refer — Patients with suspected perioperative anaphylaxis should prompt

Timing of referral — Patients should be referred to an allergy specialist as soon as possible

● A detailed description of the event, including all signs and symptoms.

● Copies of anesthesia records and surgical reports.

● Alternative anesthetic agents available for use in the facility.

The differential diagnosis of an allergic or anaphylactic reaction during or following general

Other causes of respiratory or airway symptoms

(See "Assessment of respiratory distress in the mechanically ventilated patient".)